The overall purpose of this study is to better understand how genetics contribute to transplant-related mortality after unrelated donor blood or bone marrow transplantation (BMT). BMT includes treatment with chemotherapy radiation followed by infusion of a donor's blood stem cells and is used to successfully cure otherwise fatal blood diseases. About 2 out of 3 eligible patients do not have a matched sibling donor and therefore require an unrelated donor BMT. Transplant related mortality (death due to any treatment related cause) occurs in 1 out of 3 well-matched unrelated donor BMT patients within 1-year after BMT and is a major limiting factor to offering this curative therapy to more patients. This proposed study will use a genome-wide scan to test for a genetic susceptibility to transplant related mortality in 2,800 patients, and their well-matched unrelated donors, who have received a transplant for acute leukemia or myelodysplastic syndrome at any of >150 U.S.-based BMT centers during the years 2000- 2008. The type of chemotherapy radiation and the use of high dose vs. reduced dose of chemotherapy will be tested for an interaction with the patient and/or donor's genetic makeup to determine if there is an increased or decreased risk of transplant-related mortality due to this interaction. The results will then be tested for validity in a subsequent cohort of 1,000 patient-donor pairs treated from 2009-2011. The significance of this study, if successful, is that additional genetic tests can be quickly translated to routine clinical practice which could improve patient survival after unrelated donor BMT. To date, a relationship between genetics and transplant related mortality has only been studied in a few genes and did not consider exposure to drug or dose. By performing the first comprehensive genome- wide scan with a planned test of validity, this project will improve the ability to study genetic causes for transplant-related mortality and provide preliminary support for a more tailored, individualized approach to selecting which chemotherapy drugs to use and at what dose. The data generated by this study will be shared publicly at the end of this project with the scientific and medical community to provide a unique and powerful resource for additional scientific discoveries. This proposed study addresses the American Society for Blood and Marrow Transplantation's Priority Research Area for Prognostic Indicators and Monitoring Tools. PUBLIC HEALTH RELEVANCE: This project will study the recipient and donor genetic contribution to unrelated donor blood or marrow transplant (BMT)-related mortality and provide initial support for a more tailored, individualized approach to selecting which chemotherapy drugs to use and at what dose. The goal is to improve survival after unrelated donor BMT used to treat blood diseases, which will enable more patients to receive this life- saving therapy. The data generated by this study will be shared publicly at the end of this project with the scientific and medical community to provide a unique and powerful resource for additional scientific discoveries.